B cells play a pathogenic role as antigen-presenting cells and autoantibody secretors in the lead up to T cell-mediated autoimmune destruction of insulin-producing β cells in type 1 diabetes (T1D). This has led to significant interest in the use of B cell depletion therapies as a treatment for T1D. In this review, we compare results from five recent studies that used distinct B cell-depleting agents and protocols to successfully prevent and even reverse T1D in the non-obese diabetic (NOD) mouse model. We discuss how information gained from animal studies could be used to improve on the positive outcomes of a completed phase II clinical trial of the B cell-depleting drug rituximab in humans with recent-onset T1D.